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EC number: 614-283-9 | CAS number: 68127-59-3
- Life Cycle description
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- Endpoint summary
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- Oxidation reduction potential
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- Stability: thermal, sunlight, metals
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- Dissociation constant
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- Additional physico-chemical properties of nanomaterials
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- Endpoint summary
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
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- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
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- Carcinogenicity
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- Additional toxicological data
Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 09 October 2017 to 30 October 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- reaction mass of (1R,3R)-3-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl]-2,2-dimethylcyclopropanecarboxylic acid and (1S,3S)-3-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl]-2,2-dimethylcyclopropanecarboxylic acid
- EC Number:
- 614-283-9
- Cas Number:
- 68127-59-3
- Molecular formula:
- C9H10ClF3O2
- IUPAC Name:
- reaction mass of (1R,3R)-3-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl]-2,2-dimethylcyclopropanecarboxylic acid and (1S,3S)-3-[(1Z)-2-chloro-3,3,3-trifluoroprop-1-en-1-yl]-2,2-dimethylcyclopropanecarboxylic acid
- Test material form:
- solid
Constituent 1
- Specific details on test material used for the study:
- Storage conditions: At room temperature
The dose were not adjusted for the purity of the test material.
Method
- Target gene:
- The S. typhimurium histidine (his) and the E. coli tryptophan (trp) reversion system measures his- → his+ and trp- → trp+ reversions, respectively.
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2
- Remarks:
- E.coli WP2 pKM101 and WP2 uvrA pKM101
- Details on mammalian cell type (if applicable):
- CELLS USED
- Source of cells: The bacterial strains TA1535, TA1537, TA98, TA100, WP2 uvrA pKM101, and WP2pKM101 were obtained from Trinova Biochem GmbH (35394 Gießen, Germany). Strain cultures were stored as stock cultures in ampoules with nutrient broth + 5% (MERCK, D-64293 Damrstadt) in liquid nitrogen.
- Suitability of cells: Regular checking of the properties of the S.typhimurium and E.coli strains regarding the membrane permeability and ampicillin resistance; UV sensitivity, and amino acid requirement as well as normal spontanous mutation rates are performed by the testing laboratory according to
Ames , B.N., McCann J. and Yamasaki E. (1977), Methodes for detecting carcinogens and mutagens with the Salmonella/mammalian microsome mutagenicity test, In: Klbey B.J. et al. (Eds.) "Handbook of Mutagenicity Test Procedures" Elsevi er, Amsterdam, 1-17;
Maron D.M., Ames, B.N. (1983), Revised methods for the Salmonella mutagenicity test, Mutation Res. 113, 173-215
Mortelamans K., Riccio ES. (2000), The bacterial tryptophan reverse mutation assay with Escherichia coli WP2, Mutation Res. 455 61-69
MEDIA USED
- Type and identity of media including CO2 concentration if applicable:
preculture nutrient medium: 8 g Nutrient Broth and 5 g NaCl
overlay agar for Salmonella strains: 7.0 g Agar Agar, 6.0 g NaCl, 10.5 mg L-Histidine x HCl x H2O, 12.2 mg Biotin
overlay agar for Escherichia coli strains: 7.0 g Agar Agar, 6.0 g NaCl and 10.2 mg Tryptophan
- Metabolic activation:
- with and without
- Metabolic activation system:
- Liver microsomal activation (S9 mix)
- Test concentrations with justification for top dose:
- In the pre-experiment the concentration range of the test substance tested was 3 - 5000 μg/plate. The pre-experiment is reported as Experiment I since the acceptability criteria of the assay were met. Since cytotoxic effects were observed in Experiment I, a minimum of six concentrations were tested in Experiment II. 5000 μg/plate was chosen as the maximal concentration in experiment II. The test substance was tested at the following concentrations:
Pre-experiment / Experiment I: 3; 10; 33; 100; 333; 1000; 2500; and 5000 μg/plate
Experiment II.
Strains TA 1535 and TA 98: 33; 100; 333; 1000; 2500; and 5000 μg/plate
The remaining strains: 10; 33; 100; 333; 1000; 2500; and 5000 μg/plate - Vehicle / solvent:
- - Vehicle(s)/solvent(s) used: DMSO
- Justification for choice of solvent/vehicle:DMSO (DMSO, purity 99%) was chosen because of its solubilitsation properties and its relative non-toxicity to the bacteria.
Controlsopen allclose all
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- not specified
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- methylmethanesulfonate
- other: 4-nitro-o-phenyl-diamine
- Remarks:
- without metabolic activation
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- not specified
- Positive controls:
- yes
- Positive control substance:
- other: 2-aminoanthracene
- Remarks:
- with metabolic activation
- Details on test system and experimental conditions:
- METHOD OF APPLICATION:
Experiment I was performed as a plate incorporation assay. Since negative result was obtained in this experiment, experimetn II was performed as a pre-incubation assay. According to the direct plate incorportation and pre-incubation method the bacteria are exposed to the test substance with and without metabolic activation and plated on selective medium. After a suitable period of incubation, revertant colonies are counted.
in medium; in agar (plate incorporation); preincubation; in suspension; as impregnation on paper disk
- Cell density: The optical density of the bacteria was determined by absorption measurement and the obtained values indicated that the bacteria were harvested at the late exponential or early stationary phase (10e8 -10e9 cells/mL).
- Number of Replicates: Each concentration, including the controls, was tested in triplicate.
DURATION
- Preincubation period: 60 minutes at 37°C
DETERMINATION OF CYTOTOXICITY
- Method: relative total growth
Cytotoxicity of the test substance results in a reduction of the number of spontanous revertants (below a factor of 0.5) or a clearing of the bacterial background lawn.
S9 MIX
Phenobarbital/ß-naphthoflavone induced rat liver S9 was used as the metabolic activation system. The amount of S9 supernatant was 10% v/v in the S9 mix. Co-factors are added to the S9 mix to reach the following concentrations in the S9 mix: 8 mM MgCl2, 33 mM KCl, 5 mM Glucose-6-phosphate, 4 mM NADP in 100 mM sodium-ortho-phosphate-buffer, pH 7.4 - Evaluation criteria:
- Evaluation of results: A test substance is considered as a mutagen if a biologically relevant increase in the number of revertants exceeding the threshold of twice the colony count of the corresponding solvent control is observed.
A concentration dependent increase is considered biologically relevant if the threshold is exceeded at more than one concentration.
An increase exceeding the threshold at only one concentration is judged as biologically relevant if reproduced in an independent second experiment.
A concentration dependent increase in the number of revertant colonies below the threshold is regarded as an indication of a mutagenic potential if reproduced in an independent second experiment. However, whenever the colony counts remain within the historical range of negative and solvent controls, such an increase is not considered biologically relevant.
The Salmonella typhimurium and Escherichia coli reverse mutation assay is considered acceptable if it meets the following criteria:
- regular background growth in the negative and solvent control
- the spontaneous reversion rates in the negative and solvent control are in the range of the historical data
- the positive control substances should produce a significant increase in mutant colony frequencies
- a minimum of five analysable concentrations should be present with at least four showing no signs of toxic effects, evident as a reduction in the number of revertants below the indication factor of 0.5. - Statistics:
- According to the OECD guideline 471, a statistical analysis of the data is not mandatory.
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- E. coli WP2 uvr A pKM 101
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- TEST-SPECIFIC CONFOUNDING FACTORS
Precipitation of the test substance in the overlay agar in the test tubes was observed at 5000 μg/plate with S9 mix in Experiment I and at 5000 μg/plate with and without S9 mix in Experiment II. The test substance precipitated in the overlay agar on the incubated agar plates from 2500 to 5000 μg/plate with S9 mix in both experiments. The undissolved particles had no influence on the data recording.
HISTORICAL CONTROL DATA (with ranges, means and standard deviation and confidence interval (e.g. 95%)
- Positive historical control data:
Strain TA1135: mean/SD 1130/143.1 (without S9 mix) and 388/58.2 (with S9 mix
Strain TA1537: mean/SD 82/12.7 (without S9 mix) and 191/60.8 (with S9 mix)
Strain TA98: mean/SD 378/73.7 (without S9 mix) and 3949/77.8 (with S9 mix)
Strain TA 100: mean/SD 1966/293.2 (without S9 mix) and 3798/830.4 (with S9 mix)
Strain WP2 pKM 101: mean/SD 3776/466.8 (without S9 mix) and 1355/498.3 (with S9 mix)
Strain SP2 uvrA pKM 101: Mean/SD 3364/637.1 (without S9 mix) and 2123/229.1 (with S9 mix)
- Negative (solvent/vehicle) historical control data:
Strain TA1135: mean/SD 12/2.5 (without S9 mix) and 12/2.5 (with S9 mix
Strain TA1537: mean/SD 10/2.2 (without S9 mix) and 13/3.5 (with S9 mix)
Strain TA98: mean/SD 25/4.4 (without S9 mix) and 34/6.2 (with S9 mix)
Strain TA 100: mean/SD 156/26.0 (without S9 mix) and 148/32.3 (with S9 mix)
Strain WP2 pKM 101: mean/SD 207/23.5 (without S9 mix) and 231/26.3 (with S9 mix)
Strain SP2 uvrA pKM 101: Mean/SD 334/33.0 (without S9 mix) and 378/37.7 (with S9 mix)
ADDITIONAL INFORMATION ON CYTOTOXICITY:
- Measurement of cytotoxicity used: reduction of the number of revertants (below the induction factor of 0.5)
Any other information on results incl. tables
Table 1: Cytotoxic effects, evident as a reduction in the number of revertants (below the induction factor of 0.5), were observed at the following concentration (ug/plate)
Experiment I | Experiment II | |||
without S9 mix | with S9 mix | without S9 mix | with S9 mix | |
TA 1535 | / | / | / | / |
TA 1537 | 5000 | / | 5000 | / |
TA 98 | / | / | / | 5000 |
TA 100 | / | 5000 | 5000 | 2500 -5000 |
WP2 pKM101 | 5000 | 5000 | 5000 | 5000 |
WP2 uvrA pKM101 | 5000 | 5000 | / | 5000 |
Table 2: Historical data
These data represent the laboratory´s historical control data from November 2014 until November 2016 representing approx. 600 experiments (WP2 pKM 101 and WP2 uvrA pKM 101 the historical data are based on approx. 100 experiments).
Strain |
|
Without S9 mix |
With S9 mix |
||||||
Mean |
SD |
Min |
Max |
Mean |
SD |
Min |
Max |
||
TA 1535 |
Solvent Control |
12 |
2.5 |
6 |
25 |
12 |
2.5 |
7 |
26 |
Untreated control |
12 |
3.1 |
6 |
28 |
12 |
2.9 |
7 |
26 |
|
Positiv control |
1130 |
143.1 |
334 |
1816 |
388 |
58.2 |
176 |
688 |
|
TA 1535 |
Solvent Control |
10 |
2.2 |
6 |
19 |
13 |
3.5 |
7 |
30 |
Untreated control |
11 |
2.7 |
5 |
21 |
14 |
4.0 |
7 |
31 |
|
Positiv control |
82 |
12.7 |
43 |
157 |
191 |
60.8 |
83 |
434 |
|
TA 98 |
Solvent Control Untreated control Positiv control |
25 |
4.4 |
13 |
43 |
34 |
6.2 |
15 |
58 |
27 |
4.9 |
12 |
43 |
37 |
6.5 |
11 |
57 |
||
378 |
73.7 |
211 |
627 |
3949 |
771.8 |
360 |
6586 |
||
TA 100 |
Solvent Control Untreated control Positiv control |
156 223 3776 |
26.0 23.6 293.2 |
78 79 498 |
209 217 2767 |
148 172 3798 |
32.3 25.4 830.4 |
73 85 536 |
208 218 6076 |
WP2 pKM 101 |
Solvent Control Untreated control Positiv control |
207 223 3776 |
23.5 22.7 466.8 |
171 166 2796 |
302 314 5156 |
231 230 1355 |
26.3 24.4 498.3 |
194 202 1055 |
332 334 4068 |
WP2 uvrA pKM 101 |
Solvent Control Untreated control Positiv control |
334 347 3364 |
33.0 33.2 637.1 |
242 283 1981 |
392 412 4828 |
378 392 2123 |
37.7 36.2 229.1 |
276 296 1708 |
464 483 2782 |
Mean = mean value of revertants/plate SD = standard deviation
Min = minimal value/Max = maximal value
Applicant's summary and conclusion
- Conclusions:
- In conclusion, it can be stated that during the described mutagenicity tests and under the experimental conditions reported, the test material did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used. Therefore the test material is considered to be non-mutagenic in the Salmonella typhimurium and Escherichia coli reverse mutation assay.
- Executive summary:
Study Design
This study was performed to investigate the potential of the test material to induce gene mutations in the plate incorporation test (Experiment I) and the pre-incubation test (Experiment II) using the Salmonella typhimurium (S. typhimurium) strains TA1535, TA1537, TA98, and TA100, and the Escherichia coli (E. coli) strains WP2 uvrA pKM101 and WP2 pKM101.
Results
In Experiment I the plates incubated with the test item showed normal background growth in all strains with and without metabolic activation. In Experiment II reduced background growth was observed in strains TA 1535, TA 1537 and TA 100 with and without metabolic activation.Cytotoxic effects, evident as a reduction in the number of revertants (below the induction factor of 0.5), occurred in strains TA 1537, TA 98, TA 100, WP2 pKM101, and WP2 uvrA pKM101. No increase in revertant colony numbers of any of the six tester strains was observed following treatment with CA3514 at any concentration level, neither in the presence nor absence of metabolic activation (S9 mix). There was also no observed tendency of higher mutation rates with increasing concentrations in the range below the generally acknowledged border of biological relevance. Appropriate reference mutagens were used as positive controls, which showed a distinct increase of induced revertant colonies.
Conclusion
In conclusion, it can be stated that during the described mutagenicity tests and under the experimental conditions reported, thte test material did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used. Therefore the test material is considered to be non-mutagenic in the Salmonella typhimurium and Escherichia coli reverse mutation assay.
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